Physiological and psychological stress promotes hypothalamus-pituitary-adrenal axis (HPA axis) to cause secretion of glucocorticoid (cortisol etc.) from the adrenal cortex. Glucocorticoid is known to bind to a glucocorticoid receptor (hereinafter sometimes to be referred to as “GR”) in the brain, and cause various symptoms (lowering of motivation, suppression of food ingestion, neuronal loss in the hippocampus, reduction in noradrenaline neural activity, increase of serotonin 2A receptor function, steroidal hallucination etc.) leading to the etiology of depression and the like (see non-patent document 1).
As an example of use of a compound (GR antagonist) inhibiting a bond between glucocorticoid and GR for the treatment of central nervous system diseases, mifepristone has been reported to improve the symptoms of depression (see non-patent document 2). However, mifepristone is known to show a strong progesterone receptor (hereinafter sometimes to be referred to as “PR”) antagonist action, and is feared to influence emmenia and the like.
In fact, mifepristone has been reported to show side effects in the reproductive system such as uterus convulsion and the like (see non-patent document 3).
To use GR antagonist for the treatment of central nervous system diseases such as depression and the like, the antagonist is desired to selectively act on GR and not act on other receptors.
Examples of the GR antagonist include modified pyrimidine derivative (see patent document 1), condensed azadecalin derivative (see patent document 2), triphenyl derivative (see patent document 3), phenanthrenol derivative (see patent document 4), tertiary amine derivative (see patent document 5), dihydroquinoline derivative (see patent document 6), 6-oxa-2,4-diazachrysene derivative (see patent document 7), and the like. However, there is no report relating to a GR antagonist of condensed tetrahydroquinoline compound.
On the other hand, a tetrahydroquinoline derivative having a chemical structure similar to that of a condensed tetrahydroquinoline compound has been reported (see patent document 8). However, it is not described or suggested that the derivative is effective for the treatment of central nervous system diseases.
In addition, there is a report on the binding action of a dihydroquinoline or tetrahydroquinoline derivative to GR or mineralocorticoid receptor (hereinafter sometimes to be referred to as “MR”) (see patent document 9).
However, this report does not describe at all the selectivity between such different receptors, and a tetrahydroquinoline compound wherein cyclopentyl or 5-membered heteroaryl is condensed is not described or even suggested.
Furthermore, a compound encompassing enormous combinations of structures is disclosed as a steroid receptor modulation drug (see patent document 10). However, a compound disclosed as a concrete example thereof is solely a derivative having a tetrahydroquinoline skeleton, and a tetrahydroquinoline compound wherein cyclopentyl or 5-membered heteroaryl is condensed is not described or even suggested.    patent document 1: WO2006/014394    patent document 2: WO2005/087769    patent document 3: WO2000/06137    patent document 4: U.S. Pat. No. 6,852,719    patent document 5: WO2002/064550    patent document 6: WO2004/018429    patent document 7: WO2004/110385    patent document 8: WO2003/004028    patent document 9: WO2006/19716    patent document 10: WO1996/019458    non-patent document 1: Masahiko Mikuni, Shinkei Shinpo (Advances in neurological sciences), 1998, 42(4), 656-65.    non-patent document 2: Murphy, J Psychiatry Neurosci., 1993, November; 18(5): 209-213.
non-patent document 3: Belanof, Biological Psychiatry., 2002, 52(5), 386-92.